Synthesis of substituted dibenzo(d f)azonines and intermediates

ABSTRACT

ALKOXY-SUBSTITUTED 6- AMINO-5H-DIBENZO(A,C)CYCLOHEPTENE-7-CARBONITRILES AND THEIR PREPARATION WHICH CARBONITRILES ARE USEFUL AS INTERMEDIATES IN A STEP-WISE SYNTHESIS OF 3,4&#39;&#39;,5,5&#39;&#39;-TETRAMETHOXY-DIBENZO(D,F)AZONINE AND ANALOGS.

United States Patent 3,654,343 SYNTHESIS OF SUBSTITUTED DIBENZO[d,f] AZONINES AND INTERMEDIATES Arnold Brossi, Verona, and Benjamin Pecherer, Montclair, N.J., assignors to Hoifmann-La Roche Inc., Nutley, NJ.

No Drawing. Original application Feb. 17, 1967, Ser. No. 616,803, now Patent No. 3,452,295, dated July 22, 1969. Divided and this application Apr. 10, 1969, Ser. No. 815,232

Int. Cl. C07c 65/14, 69/76 US. Cl. 260-473 R 1 Claim ABSTRACT OF THE DISCLOSURE Alkoxy-snbstituted 6 amino-SH-dibenzo [a,c] cycloheptene-7-carbonitriles and their preparation which carbonitriles are useful as intermediates in a step-wise synthesis of 3,4',5,5tetramethoxy-dibenzo [d,f]azonine and analogs.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a division of US. patent application Ser. No. 616,803, filed Feb. 17, 1967, now US. Pat. No. 3,457,295, granted July 22, 1969.

BRIEF SUMMARY OF THE INVENTION This invention relates to a novel process for the synthesis of substituted dibenzo[d,f]azonines and to novel intermediates useful therein. More particularly, the invention relates to a practical synthetic route for the preparation of compounds of the formula:

X) wherein R is lower alkyl, lower alkenyl, lower alkynyl, cyclo-lower alkyl, cycloalkyl-lower alky, aryl, aralkyl, lower alkoXy-lower alkyl or dialkylarninoalkyl; R is hydrogen, lower alkyl, lower alkoxy or benzyloxy; R is lower alkyl, lower alkoxy or benzyloxy; R and R are each independently hydrogen, lower alkyl or lower alkoxy; and R and R are each independently methyl or ethyl.

DETAILED DESCRIPTION Ce 3,654,343 Patented Apr. 4, 1972 R1 R! l l R2- -R3 R2- a RF -CHOH R4 CHEX (b) -CH2OH CHzX RaO- --0 R3 R 0 R3 T- CN R -R3 R4 -0H,0N

(e) C-NHz a) I omoN m0 ORa R50 In IE1 R R t 2' /CN R R R4 C 2 3 (e R; CHCOOR1 (f) o-ou:

l-C 2 -CHZCOOR7 R50 OR;, R -0R,

a- Ra R4- -CHzCH2X wherein the symbols R, R R R R R and R all have the same meaning as like symbols in Formula IX above; R is hydrogen or lower alkyl; and X is a leaving group such as the halogens, chlorine, bromine and iodine, and obvious equivalent leaving groups.

As used herein, the term lower alkyl" denotes straight and branched chain hydrocarbons having 1 to 7 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, tbutyl, and the like. Lower alkyl groups having 1 to 4 carbon atoms are preferred. The term lower alkoxy denotes lower alkyl ether groups wherein the lower alkyl moiety is as defined above. The term lower alkenyl denotes unsaturated hydrocarbon groups containing 1 to 7 carbon atoms and at least one double bond such as allyl, 2-butenyl, 3-butenyl, and the like. Lower alkynyl denotes unsaturated hydrocarbons having 1 to 7 carbon atoms and at least one triple bond such as 2-propynyl, 2- butynyl, 3-butynyl and the like. The term cycloalkyl denotes saturated carbocyclic groups containing 3 to 6 ring atoms. The term ary denotes phenyl and substituted phenyl groups, preferably methoxy phenyl or poly-methoxyphenyl. The term aralkyl denotes aryl-alkyl groups such as benzyl, phenethyl, methoxyphenethyl, polymethoxyphenethyl, and the like. The terms "halo, halogen, halide, and the like, denote the halogens chlorine, bromine and iodine.

The novel process of this invention as outlined above comprises the steps of:

(a) Treating a diol of Formula I with a halogenating agent such as phosphorus tribromide, phosphorus trichloride, and the like, to form a dihalide of Formula H. The reaction is suitably carried out at a temperature between about l C. and about room-temperature, though higher or lower temperatures could also be employed. It is preferred to carry out the reaction in an inert organic solvent such as an ether, e.g., diethyl ether, or a hydrocarbon solvent suchas benzene, toluene, and the like. The starting diols of Formula I are known compounds or analogs of known compounds, the preparation of which will be readily apparent to those skilled in the art by analogy to the processes for the preparation of the known starting materials.

(b) Treating the dihalide obtained in step (a) above with an alkali metal cyanide, e.g., potassium cyanide, sodium cyanide, etc., to form a diacetonitrile of Formula III. The reaction is suitably carried out in the presence of an inert organic solvent such as dimethylsulfoxide, or aqueous alcohols, and at about room temperature to about 50 C., though higher or lower temperatures could also be employed.

(0) Treating the diacetonitrile obtained in step (b) above with a catalytic amount of a base to form a cyclic aminonitrile of Formula IV. The reaction is suitably carried out in an inert organic solvent. Preferred solvents are the lower alkanols, especially ethanol. As the base catalyst there can be employed any of the strong bases such as the alkali metal hydroxides. The amount of base employed may vary from a catalytic quantity to a molecular proportion, although it is preferred to use less than 10 percent by weight based on the diacetonitrile intermediate. However, it is preferred to utilize an alkali metal alcoholate while conducting the reaction in an alcohol solvent. The reaction can be conveniently conducted at the reflux temperature of the alkanol used as the solvent, though higher or lower temperatures can also be utilized. It is preferred, however, to operate between a range of about 20 C. to about 100 C. The aminonitriles of Formula -IV are capable of imino-amino tautomerization. Both the imino and the amino forms are comprehended by this invention.

(d) Subjecting the cyclic aminonitrile of Formula IV to acid hydrolysis to obtain the hydroxynitrile of Formula V. The acid hydrolysis is readily effected with any of the usual acids. Preferred acids are the strong acids, e.g.,

mineral acids, such as hydrochloric acid, sulfuric acid, and the like. The hydrolysis can, if desired, be effected at temperatures above or below room temperature, though preferably at a temperature of about 100 C. the reaction can be carried out in the absence of any organic solvent or it can be carried out in the presence of an inert organic solvent such as a hydrocarbon solvent, for example, toluene, xylene, etc. The hydroxynitrile of Formula V is capable of keto-enol tautomerization and both the keto and enol forms are comprehended by this invention.

(e) Treating the hydroxynitrile of Formula V with an alkali metal hydroxide whereby there is obtained simultaneous saponification and ring cleavage to give the diacetic acid of Formula VI. The saponification and ring cleavage is preferably carried out at an elevated temperature in the presence of an inert organic solvent. A preferred temperature range is between about room temperature and the reflux temperature of the reaction mixture. Preferred solvents are the inert organic solvents such as lower alkanols, hydrocarbon solvents, and the like. The acid of Formula VI can be readily esteri-fied with lower alkanols. Esterification of the acids is readily effected by any of the usual techniques for esterifyiug with lower alkanols or by treatment with an alkylating agent, e.g., by treatment with diazomethane.

(f) Reduction of the diacetic acid of Formula VI by treatment with an alkali hydride/metal hydride complex, for example, with an alkali metal aluminum hydride complex or a similar complex hydride such as the aluminum or boron hydride complexes of the alkali metals such as lithium, sodium, potassium, and the like. The reduction is preferably effected with lithium aluminum hydride. The reduction is suitably carried out in the presence of an inert organic solvent such as an ether, e.g., the lower alkyl ethers, tetrahydrofuran, and the like, and preferably at a temperature between about 0 C. and 100 C.

(g) Treating the diol of Formula VII with a phosphorus halide, e.g., phosphorus tribromide, phosphorus trichloride, and the like; a hydrohalide acid, e.g., hydrobromic acid, etc.; or another equivalent reagent to form an intermediate of Formula VIII, e.g., a dihalide. The reaction is suitably carried out in an inert organic solvent such as an aromatic hydrocarbon, a lower ether or halogenated solvent, at a temperature between about l0 C. and about C.

(h) Treating the intermediate of Formula VIII obtained according to step (g) above, e.g., a dihalide of Formula VIII, with a primary amine to form the dibenzo[d,f] azonine end produts of Formula IX. The primary amines which are suitable for use in this condensation reaction are the lower alkylamiues, for example, methylamine, ethylamine, propylamine, n-butylamine, isobutylamine, t-butylamine, pentylamine, etc.; the lower alkenylamines, for example, allylamine, butenylamine, etc.; the lower alkynylamines, for example, proparglyamine, etc.; the cyclolower alkylamines, for example, cyclopropylamine, cyclohexylamine, etc.; the cyclo-lower alkyl-lower alkylamines, for example, cyclopropylmethylamine, cyclohexylmethylamine, etc.; the arylamines, for example, aniline, methoxyaniline, e.g., p-methoxyaniline, etc.; aralkylamines, for example, benzylamine, methoxybenzylamine, phenethylamine, etc.; lower alkoxy-lower alkylamines, for example, Z-ethoxyethylamine, etc.; dialkylamino-lower alkylamines, for examples, dimethylaminoethylamine, diethylaminoethylamine, etc. The condensation with a primary amine is conveniently carried out by treating the intermediate of Formula VIII with the amine reactant preferably utilizing at least a two-molar excess of the amine reactant in the presence of an acid-binding agent which can be the excess of the amine reactant or another acid-binding agent such as a hydroxide, carbonate, etc. The reaction is suitably carried out in the presence of an inert organic solvent such as a hydrocarbon solvent, for example, benzene, toluene, etc., or, if desired, where the amine reactant is a liquid, it can also be employed as solvent. The reaction temperature is not critical but it is preferred to operate at an elevated temperature, preferably at a temperature between about room temperature and about 200 C.

The intermediates of Formulae IV and V are novel compounds which constitute a part of this invention. The compounds of Formulae IV and V, as noted above, can exist in tautomeric forms. It is understood that all such forms are comprehended by the structural representation herein. The novel compounds of Formulae IV and V are, as noted above, useful as intermediates in the preparation of the pharmaceutically useful dibenzo[d,f]azonines of Formula IX.

The invention will be more fully understood from the examples which follow. These examples are intended to illustrate the invention and are not to be construed as limitative thereof.

EXAMPLE 1 Preparation of a,a'-dibromo-3,4',5,5'-tetrarnethoxyo,o'-bitolyl To a stirred suspension of 70 g. (0.21 moles) of 3,4',5, 5'tetramethoxybiphenyl-2,2'-dimethano1 in '-2.1 l. of dry ether, 56.8 g. (0.21 moles) of phosphorus tribromide was added dropwise at 4 to over a 20 min. period, and then the mixture was allowed to warm to room temperature. After 24 hours of stirring a dense white solid had precipitated. The suspension was poured into ice water, 1 l. of benzene was added and the mixture stirred until all the solid had dissolved. The organic phase was washed succesively with water, saturated bicarbonate solution, water and dried. Removal of the solvent at reduced pressure yielded OL,OL' dibromo-3,4',5,5'-tetramethoxy-o,o'-bitolyl as a buff solid, M.P. 118120. After recrystallization from petroleum ether the product was obtained as white crystals of M.P. 124-126. IR (CHCI 3000, 2940, 2830, 1603, 1520 cm.-

Analysis-(Salad. for C H Br O (percent): C, 46.98; H, 4.38; Br, 34.73. Found (percent): C, 46.89; H, 4.63; Br, 34.84.

EXAMPLE 2 Preparation of 3,4,5,5'-tetramethoxy-2,2-biphenyldiacetonitrile One hundred and seventy grams (0.37 moles) of a,oz' dibromo-3,4',5,5'-tetramethoxy-o,o'-bitolyl was added to a stirred suspension of 76 g. (1.11 moles) of potassium cyanide (95%) in 3.1 of dimethyl-sulfoxide. The temperature rose to 30 and after 45 min. at this temperature, the mixture was poured into ice-water with vigorous stirring, whereupon the initially formed oil solidified. The solid was collected by filtration, washed with water and dried giving 3,4,5,5-tetramethoxy-2,2'-biphenyl diacetonitrile, M.P. 105107. Recrystallization from ethanol gave the product as tan crystals, M.P. 109-111. A colorless analytical sample was obtained by one more recrystallization from ethyl acetate-petroleum ether (60-90), M.P. 1l6.5-118.5. IR (CHCl 3005, 2960, 2930, 2840, 2245, 1600, 1520 cm.-

Analysis.-Calcd. for C H N O (percent): C, 68.17; H, 5.72; N, 7.95. Found (percent): C, 67.92; H, 5.98; N, 8.04.

EXAMPLE 3 Preparation of 6-amino-2,4,9,10-tetramethoxy-5H-dibenzo [a,c] cycloheptene-7-carbonitrile Sixty-four grams of 3,4',5,5'-tetramethoxy-2,2-biphenyldiacetonitrile was dissolved in 700 ml. of boiling ethanol and 10.9 ml. of a 3% solution of sodium ethoxide was added. After 2 hrs. of refluxing, the solution was chilled for 18 hrs. The crystalline solid which separated was collected, washed with ethanol and dried to yield 6-amin0 2,4,9,10-tetramethoxy 5H dibenzo[a,c]cycloheptene-7- carbonitrile as a white solid, M.P. l97l98. IR (KBr): 3450, 3350, 3220, 2930, 2828, 2190, 1635, 1588, 1513 cmr Analysis.-Calcd. for C H N O (percent): C, 68.17; H, 5.72; N, 7.95. Found (percent): C, 68.23; H, 6.02; N, 7.82.

EXAMPLE 4 Preparation of 6,7-dihydro-2,4,9,l0-tetramethoxy-6-oxo- 5H dibenzo[a,c]cycloheptene 7 carbonitrile 6- hydroxy-2,4,9,IO-tetramethoxy 5H-dibenz0[a,c]cycloheptene-7-carbonitrile Sixty-four grams of 6-amino-2,4,9,10-tetramethoxy-5H- dibenzo[a,c]cycloheptene-7-carbonitrile was refluxed for 0.5 hr. with 1.82 l. of 6 N hydrochloric acid and a few ml. of xylene. The suspension was chilled for one hr., the solid was collected, Washed free of acid and dried. This product (64 g., M.P. 216-2l8) after recrystallization from ethanol, melted at 220221.5. The IR (KBr) showed a sharp band at 3585, others at 3010, 2960, 2940 2250, 2200, 1740, 1610 and 1510 cmr which indicated that in the solid state the substance is a keto-enol mixture of 6,7-dihydro-2,4,9,10-tetrameth0xy-6-oxo-5H dibenzo[a,c]cycloheptene-7-carbonitrile and 6-hydroxy-2,4, 9,10-tetramethoxy-5H'dibenzo[a,c]cycloheptene 7 carbonitrile.

Analysis.Calcd. for C H NO (percent): C, 67.98; H, 5.42; N, 3.96. Found (percent): C, 67.66; H, 5.59; N, 3.86.

EXAMPLE 5 Preparation of 3,4,5,5'-tetramethoxy-2,2-biphenyldiacetic acid A suspension of 64 g. (0.181 mole) of 6,7-dihydro- 2,4,9,10tetramethoxy 6 oxo 5H dibenzo[a,c] cycloheptene-7-carbonitrile in a mixture of 640 ml. of 30% sodium hydroxide and 400 ml. of methanol was refluxed for 24 hrs. The cooled, turbid solution was diluted with 2 l. of Water and extracted with two 300 ml. portions of ether. Acidification of the aqueous layer precipitated an oil which was extracted with three 300 mLportions of chloroform. The combined extracts .were washed with water and dried. Distillation of the solvent under reduced pressure gave an oily residue which solidified when triturated with ethyl acetate. Filtration gave 3,4',5,'5'-tetramethoxy-2,2'-biphenyldiacetic acid as a white solid, M.P. 193.5194.5 which after recrystallization from ethyl acetate melted at 197-198. IR (KBr): 2950, 2435, 1710, 1605, 1590, 1515 cmr Analysi.r.Calcd. for C H O (percent): C, 61.53; H, 5.68. Found (percent): C, 61.84; H, 5.59.

EXAMPLE 6 Preparation of dimethyl ester of 3,4',5,5-tetramethoxy- 2,2-biphenyl-diacetic acid The 3,4',4,5-tetramethoxy-2,2'-bipheny1 diacetic acid was esteri fied in methanol with an excess of diazomethane. Recrystallized from methanol, the ester melted at -1015". IR (CHCl 3025, 2935, 2835, 1730, 1610, 1515 cmr Analysis.Calcd. for C H O' (percent): C, 63.15; H, 6.26. Found (percent): C, 63.18; H, 6.37.

EXAMPLE 7 Preparation of 3,4,5,5-tetramethoxy-2,2'-biphenyl diethanol A solution of 59.4 g. (0.152 mole) of the diacetic acid in 610 ml. of tetrahydrofuran was added dropwise to a stirred suspension of 22.8 g. (0.608 mole) of lithium aluminum hydride in 610 ml. of tetrahydrofuran. The mixture was refluxed for 2 hrs., decomposed in the usual way with water, and then filtered (filter 'aid). From the filtrate, after removal of the solvent, 20 g. of an oil was obtained that was dissolved in ethyl acetate. Chilling yielded 3,4',5,5-tetramethoxy 2,2 biphenyl diethanol, M.P. 127-128. The cake of oxides was dissolved in 10% hydrochloric acid, the filter aid removed, the filtrate shaken with chloroform, and the aqueous layer discarded. The chloroform layer was washed successively with water, saturated bicarbonate solution, Water, and dried. Removal of the solvent gave an oil that on crystallization from ethyl acetate yielded additional 3,4',5,5-tetramethoxy- 2,2-biphenyl diethanol, M.P. 127128. An analytical sample was obtained by recrystallization from ethyl acetate-petroleum ether (60-80"), M.P. 126l27. IR (CHCl 3590, 3500-3330, 3000, 2940, 2820, 2440, 2400, 1600, 1515 cmr Analysis.-Calcd. for C H Q (percent): C, 68.28; H, 7.23. Found (percent): C, 66.57; H, 7.02.

7 EXAMPLE 3 Preparation of 2,2-bis(2-brornoethyl)-3,4,5,5'-tetramethoxy-biphenyl One gram (0.00276 mole) of 3,4',5,5'-tetramethoxy- 2,2-bipheny1 diethanol was suspended in 28 ml. of dry ether and cooled to 0.75 g. (0.00276 mole) of phosphorus tribromide was added dropwise. After 10-15 min. a viscous material separated. Addition of an equal volume of benzene rendered the mixture homogeneous. The mixture was poured into 50 ml. of ice water, the organic layer washed with cold water and dried. Distillation of the solvent gave an oil which was dissolved in 3 ml. of benzene and the solution passed through a bed of g. of Woelm alumina Grade I. The alumina was washed with 150 m1. of benzene and after removal of the solvent from the combined eluates, 100 mg. of a colorless oil was obtained. The oil solidified to give 2,2'-bis(2-bromoethyl)-3,4,5,5'-tetramethoxybiphenyl, M.P. 89-91". Recrystallization from petroleum ether (6090) raised the M.P. to 91-92. IR (KBr): 3000, 2940, 2830, 1605, 1580, 1515 cm.-

Analysis.Calcd. for C H Br O (percent): C, 49.20; H, 4.95; Br, 32.75. Found (percent): C, 48.99; H, 5.01; Br, 32.85.

EXAMPLE 9 Preparation of 6,7,8,9-tetrahydro-2,3,10,12-tetrarnethoxy- 7-methyl-5H-dibenz [d,f azonine Two hundred and fifty milligrams of 2,2'-bis(2-bromoethyl)-3,4,5,5'-tetramethoxybiphenyl was heated for 2 hours at 140-150 with a solution of 0.5 g. of methylamine in 10 ml. of benzene under 200 lbs. of nitrogen pressure. The bases were extracted into 10% hydrochloric acid, liberated with excess potassium hydroxides, and taken up in ether. The ethereal solution was dried and the solvent distilled to leave 170 mg. of a pale colored syrup which crystallized on standing overnight. The solid was dissolved in 3 ml. of benzene and passed over 10 g. of Woelm alumina, Grade II. Elution with ml. of benzene gave 6,7,8,9-tetrahydro-2,3,l0,l2-tetramethoxy-7- methyl-5H-dibenz[d,f] azonine as a white crystalline solid, M.P. 84-86".

Analysis.-Calcd. for C H NO (percent): C, 70.56; H, 7.61; N, 3.92. Found (percent): C, 70.66; H, 7.84; N, 4.19.

We claim:

1. A compound of the formula Cll COOR R4 CH COOK-r JAMES A. PATTEN, Primary Examiner J. F. TERAPANE', Assistant Examiner US. Cl. X.R. 260520 

